Is APOE p.Arg154Leu (c.461G>T) pathogenic?

APOE p.Arg154Leu (c.461G>T) is classified Likely pathogenic in APOE (ClinVar, Single submitter, 1 submitter; last evaluated 2015-12-21). AlphaMissense: ambiguous (0.3653); Absent from gnomAD v4.1; Associated with Abnormal circulating lipid concentration.

What condition is associated with APOE p.Arg154Leu (c.461G>T)?

APOE p.Arg154Leu (c.461G>T) is associated with Abnormal circulating lipid concentration (ClinVar).

How common is APOE p.Arg154Leu (c.461G>T) in the general population?

APOE p.Arg154Leu (c.461G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about APOE p.Arg154Leu (c.461G>T)?

AlphaMissense predicts ambiguous (score 0.3653) — an in-silico prediction, not a clinical call.

APOE p.Arg154Leu

c.461G>T · rs200703101 · VCV375636

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3653 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,559,966)

Conditions

Abnormal circulating lipid concentration

Computational evidence

Protein change
AlphaMissense	0.3653	ambiguous
REVEL	0.602	indeterminate
SaProt	LLR -9.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,622 bp · p 0.6 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,559,966). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: APOE
Protein: p.Arg154Leu
Coding: c.461G>T
MANE Select: NM_000041
dbSNP: rs200703101
Type: single nucleotide variant
Location: chr19:44908757 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 31 PDB
Residue 154: the '8 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in hlpp3; apoe2-type); a UniProt-annotated variant site (in hlpp3; apoe2 christchurch; decreased binding to ldl receptor); an α-helix

Full APOE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Abnormal circulating lipid concentration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APOE p.Arg154Ser Pathogenic/Likely pathogenic ★★ same residue
APOE p.Arg154His Likely pathogenic ★ ⚠ same residue
APOE p.Arg154Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
APOE p.Arg154= Likely benign ★ same residue
APOE p.Arg43Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
APOE p.Trp228Ter Likely pathogenic ★★ same type
APOE p.Arg246Pro Uncertain significance ★★ ⚠ same type
APOE p.Arg269Gly Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/apoe-p-arg154leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown